Bipolar disorder is a chronic and often debilitating disease. Lithium and Valproate remain the most widely used mood stabilizing agents in this disorder. However, they are not effective for everyone and they cause significant side effects. Valproate is known to be an inhibitor of histone deacetylase (HDAC) proteins and recent studies also find that lithium treatment leads to a downregulation of certain HDACs. Using a mouse that displays many features characteristic of human disorder, we have found that both lithium and valproate lead to a reversal of their abnormal phenotypes. Furthermore, if we treat these mice with much more selective HDAC inhibitors, we find that these are also capable of normalizing their manic-like phenotypes. Moreover, in previous studies we determined that lithium treatment leads to an increase in histone acetylation at the promoter of the Cholecystokinin (Cck) gene in the ventral tegmental area (VTA) and that these changes in histone acetylation are important in the therapeutic response. These data led us to hypothesize that selective HDAC inhibitors might be therapeutic in the treatment of bipolar disorder and because of their selectivity, they will hav far fewer side effects than valproate which inhibits many different HDACs and alters the function of other proteins. Thus in this proposal we will test compounds on our mice which are highly selective for only one or two specific class I HDAC proteins. If these compounds are successful at reversing the manic-like phenotype of the mutant mice, then they, or others like them, could move forward into clinical trials for the treatment of bipolar disorder. In addition to the direct translational studies, we want to understand the mechanisms by which these HDAC inhibitors are working. We are focusing on the VTA as a potential site of action for these compounds since this area is enriched in dopaminergic neurons and dopamine is thought to be keenly involved in the precipitation of manic episodes. Moreover, we are using viral mediated gene transfer to knock-down the expression of individual class I HDAC proteins in the dopamine neurons of the VTA to determine if we can identify exactly which HDAC (or HDACs) need to be inhibited to produce a therapeutic effect. We will also look at the changes in histone acetylation that occur in response to pharmacological inhibition both globally in the VTA and specifically at the Cck promoter. Finally, since Cck is not the only gene that is altered by valproate treatment, we plan to use a combination of next generation sequencing techniques to determine the important target genes that are enhanced in the dopamine neurons of the VTA following treatment with HDAC inhibitors. This will lead us to other potential targets for future treatment development.